Ethyl (3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)acetate (etozoline) is a known compound [see Liebigs Ann. Chem., 665, 150(1963)] and its diuretic action has also already been described.
This compound contains an asymmetric carbon atom in the 5-position; thus, etozoline is a racemate. Because of the particular structural characteristics of etozoline, the separation of the racemate into its optically active isomers has hitherto not been carried out for certain technical reasons. Etozoline is a very weak base which does not form salts with the usual chiral acids, for example (+)-tartaric acid, (+)-dibenzoyltartaric acid and (+)-camphorsulphonic acid. Thus, this racemate has not been separated by known methods.
Esterification of the known, optically-active (+)-(3-methyl-4-oxo-5N-piperidinothiazolidin-2-ylidene)-acetic acid [(+)-ozolinone (see Federal Republic of Germany Patent Specification No. 26 58 858)] also cannot be carried out with agents which can be used on a large scale because it racemizes under the esterification conditions. Thus, for example, (+)-ozolinone racemizes to an extent of 15% in 0.1N hydrochloric acid in less than 1 hour. Even in chloroform, in the same period of time, the degree of racemization which occurs is about 10%.
We have now surprisingly found that (+)-ozolinone can be esterified without racemization via the acid chloride. Thus, pure (+)-etozoline is obtained when a solution of the free (+)-carboxylic acid [(+)-ozolinone] is quickly mixed at a low temperature with an excess of a compound chosen from among thionyl chloride phosphorous oxychloride, phosphorous pentachloride and phosphorous trichloride; thereafter anhydrous ethanol, also in excess, is added thereto. In the case of this method of esterification, surprisingly, no racemization takes place and pure (+)-etozoline is obtained.
The method according to the present invention has also proved to be useful for the preparation of other optically pure esters of ozolinone and permits the large scale preparation of these optically-active compounds in an especially favorable one-pot process.